Cystic fibrosis (CF) is a hereditary disease that is linked to a defective cystic fibrosis transmembrane receptor (CFTR) (Raman et al., (2002) Pediatrics 109: e19. In CF patients, the presence of a defective CFTR protein leads to dehydrated mucosal surfaces and disruption of ion transport. In the initial stages of disease, CF patients are infected with Staphylococcus aureus and Hemophilus influenzae, but eventually become infected with nonmucoid Pseudomonas aeruginosa, a gram-negative opportunistic pathogen that is the major cause of morbidity and mortality in these patients (Burns et al., (2001) J. Infectious Diseases 183:444-452; Koch, (2002) Pediatr. Pulmonol. 34:232-236; Li et al., (2005) JAMA 293:581-588; Tosi et al., (1995) J. Infectious Diseases 172:453-461). Following colonization, P. aeruginosa undergoes a mucoid conversion to an alginate-overexpressing phenotype that is associated with biofilm development and enhanced resistance to antibiotic therapy (Li et al., (2005) JAMA 293:581-588). CF is characterized by lung inflammation mediated, in part, by chronic P. aeruginosa infection. P. aeruginosa possess numerous virulence factors that facilitate evasion of the immune system (Frank et al., (2002) J. Infectious Diseases 186: 64-73; Morici et al., (2007) J. Bacteriology 189:7752-7764; Nicas & Iglewski, (1985) Can. J. Microbiol. 31:387-392; Sadikot et al., (2005) Am. J. Respiratory and Critical Care Medicine 171:1209-12223). For example, P. aeruginosa secrete enzymes such as alkaline protease and elastase, which degrade complement components and thus limit the role of complement in the clearance of early pulmonary P. aeruginosa infections (Gross et al., (1978) J. Clin. Invest. 62:373-378). The critical role of complement in the clearance of P. aeruginosa is evidenced by the observation that C3 and C5 knock-out (KO) mice were unable to clear P. aeruginosa after challenge (Mueller-Prtiz et al., (2004) Infect. Immun. 72:2899-2906; Younger et al., (2003) Am. J. Resp. Cell Molecular Biology 29:432-438). In addition, P. aeruginosa express LPS variants that interfere with C3b deposition (Schiller, (1988) Infect. Immun. 56:632-639).
Initial efforts to develop a P. aeruginosa vaccine focused primarily on LPS. Although vaccination with P. aeruginosa lipopolysaccharide (LPS) was effective in several animal models and led to the production of highly opsonic antibodies, the efficacy in human trials was limited by antigenic diversity of O-antigens among P. aeruginosa (DiGiandomenico et al., (2007) Proc. Nat. Acad. Sci. USA 104:4624-4629).
P. aeruginosa possesses two types of flagellins, type-A and type-B that differ in amino acid composition and length of the hypervariable region. A phase III clinical trial of P. aeruginosa flagella in CF patients demonstrated that the vaccine was well tolerated, but only resulted in a 30% reduction in the incidence of infection (Döring et al., (2007) Proc. Nat. Acad. Sci. 104:11020-11025). In related studies, immunization with the OprI antigen of P. aeruginosa and an alum adjuvant elicited a protective response in mice that correlates with the titer of OprI-specific IgG (Finke et al., (1990) Infect. Immun. 58:2241-2244). In addition, an adenovirus expressing epitope 8 (amino acids 310-340) (Epi8) of OprF provided protection against acute P. aeruginosa infection (Worgall et al., (2007) J. Virol. 81:13801-13808; Worgall et al., (2005) J. Clin. Invest. 115:1281-1289). Several investigators have focused on a fusion peptide containing OprF and OprI as a potential vaccine candidate. A study in burn patients revealed that a OprF-OprI fusion peptide was immunogenic and well tolerated (Knapp et al., (1999) Vaccine 17:1663-1666; Mansouri et al, (2003) FEMS Immunology and Medical Microbiology 37:161-166).
Although these experimental P. aeruginosa vaccines have shown some promise in initial clinical trials, none have achieved the level of response required for protection against P. aeruginosa in CF patients.
It would be desirable to provide improved reagents, pharmaceutical formulations and methods for producing an immune response against P. aeruginosa, for example, to prevent and/or treat infection (e.g., in CF patients, burn patients or ventilated patients).